System and method for preventing alopecia

ABSTRACT

Traction alopecia and other disorders related to mechanical pulling on hair are treated or prevented by administering a topical composition comprising an alpha-1 adrenergic receptor agonist, a muscarinic receptor agonist, a nicotinic receptor agonist, and/or a cholinesterase inhibitor, or electrical stimulation to contract the arrector pili muscle. Compositions and methods are disclosed herein for the treatment and prevention of hair loss disorders caused at least in part by repeated application of tensile force to hair, including, without limitation, traction alopecia.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation-in-part application of, and claimsthe benefit of, PCT/US2015/060663 (WO 2016/077744) filed Nov. 13, 2015,which claims the benefit of U.S. Provisional Application No. 62/080,137filed on Nov. 14, 2014, U.S. Provisional Application No. 62/099,830filed on Jan. 5, 2015, U.S. Provisional Application No. 62/213,355 filedon Sep. 2, 2015, and U.S. Provisional Application No. 62/221,863 filedon Sep. 22, 2015. The entire content of each application referencedabove is incorporated herein by reference.

FIELD

The present invention is directed to methods for treating, reducing orpreventing alopecia and other hair loss disorders caused by mechanicalpulling of the hair, including but not necessarily limited to tractionalopecia, and compositions, devices and kits useful in such methods.

BACKGROUND

Traction alopecia results from the chronic application of tensile forceto scalp hair (1). The condition was described as early as 1907 insubjects from Greenland who had developed hair loss due to prolongedwearing of tight ponytails (2). Traditionally, the term “tractionalopecia” has been related to specific hairstyles that cause increasedtension on the scalp (e.g., ponytails, Afro-Caribbean hair styles withtight braiding or the tightly wound turbans of Sikh men). It has alsobeen seen in female ballerinas. It is also seen in cultural traditionswhere the hair is voluntarily not cut in religious obeisance, whichcauses progressively increasing weight of the hair itself. Tractionalopecia is mechanical in etiology, rather than androgenic. Managementincludes cessation of the chronic traction. However, this isunacceptable to people who favor the specific hairstyles and stylingtechniques that give rise to the condition.

Traction alopecia is a substantial risk in hair extensions and weaves,which can be worn either to conceal hair loss, or purely for cosmeticpurposes. The latter involves creating a braid around the head below theexisting hairline, to which an extended-wear hairpiece, or wig, isattached. Because the hair of the braid is still growing, it requiresfrequent maintenance, which involves the hairpiece being removed, thenatural hair braided again, and the piece snugly reattached. The tightbraiding and snug hairpiece cause tension on the hair that is already atrisk for falling out. Traction alopecia is one of the most common causesof hair loss in African American women. “Traction alopecia” includeshair loss or shedding due to increased traumatic force on hair folliclescaused by hairstyle or mechanical hair procedures such as blow drying,flat ironing, hair curling and chronic brushing. Traction alopecia canalso develop in patients constantly pulling their hair such as intrichotillomania.

In traction alopecia, affected areas depend on the etiology of thedisorder, but usually hair loss is localized on frontal and temporalscalp. According to population studies in African women, prevalence oftraction alopecia varies from 17.1% in young women (6-21 years) to 31.7%in older women (18-86 years). Clinical features of traction alopeciainclude itching of the scalp, perifollicular erythema, scaling,folliculitis, and pustules, but it can also present as slow onset ofhair loss without other symptoms. Primarily, traction alopecia isconsidered noncicatricial, yet excessive tension can lead to permanentalopecia, due to physical damage of hair follicles. Prolonged force onhair follicles may lead to inflammatory changes in immune cellinfiltrate and fibrosis can result. Therefore, it is important torecognize the condition early, while it is still reversible.

In view of the popularity of hairstyles that result in tractionalopecia, and the desirability of use of hairstyling and care productsthat may cause traction alopecia, there is a need for treatment andprevention of hair loss associated with the condition.

SUMMARY

Compositions and methods are disclosed herein for the treatment andprevention of hair loss disorders caused at least in part by repeatedapplication of tensile force to hair, including, without limitation,traction alopecia. Such disorders may be treated or prevented by theapplication to the hair follicle or scalp of a pilomoter effectiveamount of an active agent selected from the group consisting of alpha 1adrenergic receptor agonists (A1AR agonists), muscarinic receptoragonists, nicotinic receptor agonists, and cholinesterase inhibitors. Inone embodiment, the active agent is selected from the group consistingof muscarinic receptor agonists, nicotinic receptor agonists, andcholinesterase inhibitors.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings exemplify embodiments of the present inventionand, together with the description, serve to explain and illustrateprinciples of the invention. The drawings are intended to illustratemajor features of the exemplary embodiments in a diagrammatic manner.The drawings are not intended to depict every feature of actualembodiments nor relative dimensions of the depicted elements, and arenot drawn to scale.

FIG. 1a depicts a cross sectional view of the hair follicle and thearrector pili muscle in a relaxed state; and

FIG. 1b depicts a cross sectional view of the hair follicle and thearrector pili muscle in a tensed state.

FIGS. 2 and 3 depict hair loss from mechanical pulling according to theexperiment reported in example 3.

FIGS. 4 and 5 depict epilatory force thresholds on scalp hair folliclesfollowing topical phenylephrine application according to the proceduresdescribed in example 3.

DETAILED DESCRIPTION

Each hair follicle in the scalp contains an arrector pili muscle (alsoreferred to as “AP” herein) that, when contracted, erects the hair. Thesmooth muscle in the arrector pili expresses α1 adrenergic receptors(“A1AR”). Agonists of the adrenergic receptors directly stimulate thesmooth muscle. Also, acetylcholine and acetylcholine receptor agonistsact via axon reflexes to stimulate smooth muscle contraction.Acetylcholine acts on the nerves in the central nervous system as asubstance mediating the propagation of impulses across the ganglionicsynapse, but it also has a second pharmacological effect, which ismediated through an axon reflex. Axon reflexes are peripheral nervoussystem impulses independent of the central nervous system. See Rothmanand Coon, “Axon Reflex Responses to Acetyl Choline in the Skin,” J.Investigative Dermatology, 3: 79-97 (1940). Without limiting theinvention in any way, it is believed that the smooth muscle in thearrector pili is served by or associated with both noradrenergic fibersand a cholinergic system, and therefore agents that stimulate release oftransmitters from these systems or that activate the axon reflex can beused to stimulate smooth muscle contraction and thereby increase theepilation force needed to remove hair. As shown herein, such activeagents protect against hair loss or shedding as shown by an increase inepilation force needed to remove a hair and reduction in the number ofhairs removed after brushing. Without intending to be limited or boundby theory, Applicants postulate that contraction of the arrector pilimuscle via an A1AR receptor agonist, a muscarinic receptor agonist, anicotinic receptor agonist, and/or a cholinesterase inhibitor increasesthe threshold of force required to pluck hair during cosmetic proceduresand while under mechanical stress. Thus, it is believed that thecompounds and agents used in the present invention stimulate contractionof the AP muscle and thereby reduce hair loss by increasing the forcerequired to remove the hair.

Thus, alpha-1adrenergic agonists and cholinergic receptor agonists,including, but not limited to muscarinic receptor agonists, nicotinicreceptor agonists, and acetylcholine and other neurotransmitters thatstimulate smooth muscle contraction are contemplated for use in themethods and compositions described herein. Another manner ofaccomplishing smooth muscle contraction is by reducing the destructionof acetylcholine following its release by administering one or morecholinesterase inhibitors. Disclosed herein are methods for thetreatment and prevention of disorders associated with mechanical stressor pulling on the hair comprising topical administration to the scalp orhair follicle of a an effective amount of a composition comprising oneor more A1AR receptor agonists, muscarinic receptor agonists, nicotinicreceptor agonists, and/or cholinesterase inhibitors.

The use of A1AR agonists to promote the pilomotor effect is described inU.S. Pat. No. 4,853,216, which is incorporated herein by reference inits entirety. There, the A1AR agonists were recognized as useful forcausing hairs to stand up to facilitate closer shaving or to potentiatethe effect of depilatories. That is, A1AR agonists were described thereas agents that facilitate hair removal, as opposed to prevent hair loss.

While the disclosure most often specifically refers to A1AR agonists,muscarinic receptor agonists, nicotinic receptor agonists,acetylcholine, and cholinesterase inhibitors as agents useful fortreating and preventing the disorders described herein relating to hairloss, it should be understood that any agent that stimulates contractionof smooth muscle, and particularly the AP muscle, can be useful in thecompositions and methods described herein.

As used herein, the term “traction alopecia” means a form of alopecia(hair loss or hair shedding) associated with mechanical forces that pullthe hair such as hair brushing hair combing, flat ironing, wearing ofextensions, hair braiding, and ponytail style hair. Under thisdefinition, although chronic traction on the hair can lead to tractionalopecia, the mechanical forces that pull the hair do not necessarilyneed to be chronic to lead to hair loss or excessive shedding.

As used herein, the term “pilomotor effective” refers to an agent ortreatment that stimulates contraction of the arrector pili muscleassociated with a hair follicle. A “pilomotor effective amount” of anagent or treatment is an amount sufficient to stimulate contraction ofthe arrector pili muscle.

As used herein, the term “alpha 1 adrenergic receptor agonist” or “A1ARagonist” refers to a ligand that binds the alpha 1 adrenergic receptoron smooth muscle cells and activates smooth muscle contraction.

As used herein, the terms “prevent” or “prevention” and otherderivatives of the words, when used in reference to alopecia, e.g.,traction alopecia, refer to a reduced likelihood of alopecia in anindividual receiving a given treatment relative to that of a similarindividual at risk for alopecia but not receiving that treatment. Assuch, the terms “prevent” and “prevention” encompass a treatment thatresults in a lesser degree of alopecia, e.g., traction alopecia, thanwould be otherwise expected for a given individual. Efficacy forprevention of alopecia, e.g., traction alopecia, can be establishedthrough controlled studies, e.g., in which a subject is administered atreatment (e.g., a topical treatment) at one site likely to experienceor exhibit alopecia (e.g., for traction alopecia, a site at which hairis pulled for an extended period of time) but not at another sitesubjected to the same conditions. Under these circumstances, if the sitetreated with the topical treatment undergoes less hair loss over timerelative to the untreated site, e.g., at least 5% less, at least 10%less, at least 15% less, at least 20% less, at least 25% less, at least30% less, at least 35% less, at least 40% less, at least 45% less, atleast 50% less or beyond, the treatment is effective for the preventionof alopecia, e.g., traction alopecia. Efficacy for the prevention ofother forms of alopecia can be established in a similar manner, e.g., bytreating one area affected by or likely to be affected by such alopecia,but not another, substantially similar area (i.e., subject to the sameconditions causing alopecia or a likelihood of alopecia) and comparinghair loss or retention in the two areas.

As used herein, the terms “treat,” “treatment,” or “treating” refer totherapeutic treatments, wherein the object is to reverse, alleviate,ameliorate, inhibit, slow down or stop the progression or severity of adisease or condition, e.g., traction alopecia or other form of alopecia.The term “treating” includes reducing or alleviating at least oneadverse effect or symptom of a disease or condition, e.g., tractionalopecia or other form of alopecia. Treatment is generally “effective”if one or more symptoms are reduced. Alternatively, treatment is“effective” if the progression of a disease is reduced or halted. Thatis, “treatment” includes not just the improvement of symptoms, but alsoa cessation of, or at least slowing of, progress or worsening ofsymptoms compared to what would be expected in the absence of treatment.Beneficial or desired clinical results include, but are not limited to,alleviation of one or more symptom(s), diminishment of extent ofdisease, stabilized (i.e., not worsening) state of disease, delay orslowing of disease progression, amelioration or palliation of thedisease state, remission (whether partial or total), and/or decreasedmortality. For example, treatment is considered effective if the extentor amount of hair loss is reduced, or the progression of hair loss isslowed or halted. The term “treatment” of a disease also includesproviding relief from the symptoms or side-effects of the disease(including palliative treatment).

As used herein, the term “epilatory” relates to the removal of hair. Asused herein, the term “increasing epilatory force” refers to anytreatment that increases the physical force required to remove a hair.As noted, the increase in force can be viewed as at least a partialbalancing of a traction force by the force exerted by the arrector pilimuscle—the vector direction of the arrector pili muscle's force ofcontraction need not necessarily be directly opposed to a traction forceon the hair shaft to increase the epilatory force required to remove thehair, but the net effect is that the muscle provides at least a partialcounter-acting force to the traction force, whether it directly pullsback on the hair or simply holds the hair or hair follicle more tightlyin place. An increase in epilatory force can be measured in severalways, including empirically, through a reduction in traction alopecia(e.g., 10% or less reduction in hair loss) despite continued or ongoingtraction, or through measurement of actual force exerted on the hairfollicle, e.g., with a myograph, trichotilometer, or a device used tomeasure tensile forces.

As used herein the tem “comprising” or “comprises” is used in referenceto compositions, methods, etc. refers to component(s) or method stepsthat are present in the method or composition, yet allows for thecomposition, method, etc. to also include unspecified elements.

The term “consisting of” refers to compositions, methods, and respectivecomponents thereof as described herein, which are exclusive of anyelement not recited in that description of the embodiment.

As used herein the term “consisting essentially of” refers to thoseelements required for a given embodiment. The term permits the presenceof elements that do not materially affect the basic and novel orfunctional characteristic(s) of that embodiment.

The singular terms “a,” “an,” and “the” include plural referents unlesscontext clearly indicates otherwise. Similarly, the word “or” isintended to include “and” unless the context clearly indicatesotherwise. Although methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of thisdisclosure, suitable methods and materials are described below. Theabbreviation, “e.g.” is derived from the Latin exempli gratia, and isused herein to indicate a non-limiting example. Thus, the abbreviation“e.g.” is synonymous with the term “for example.”

In various aspects, the technology described herein relates to theprevention of traction alopecia. One preventive approach currentlyavailable for traction alopecia is to remove, limit or avoid theapplication of a traction force to the hair. Thus, hairstyles or otherfactors that pull on the hair (e.g., tight fitting helmets) shouldnormally be avoided to prevent traction alopecia. However, by using themethods set out herein, one can limit, reduce or prevent as that term isdefined herein the traction alopecia-inducing effects of such hairstylesor factors despite the ongoing traction involved. This preventiveapproach permits one to wear a hairstyle, helmet, etc., that wouldnormally have a high risk of inducing traction alopecia without actuallysuffering the traction-related hair loss.

Various aspects of the technology described herein involve pilomotorstimulation. The measurement or detection of pilomotor stimulation canbe performed, at its simplest, by observation of the area at the base ofthe hair shaft—an agent or treatment that induces arrector pilicontraction causes the hair follicle to “stand up” and causes puckeringof the skin around the hair shaft commonly referred to as “goose bumps.”Thus, if an agent is applied and the hair stands up, goose bumps form,or both, the agent has stimulated the arrector pili. Measurement of thestrength of arrector pili muscle contraction can be performed, ifnecessary, via myograph adapted for that purpose. Examples are describedin, e.g., Zeveke & Gladysheva, Bull. Exp. Biol. Med. 71: 102-105 (1971);Hellmann, J. Physiol. 169: 603-620 (1963); Wyness L A, McNeill G,Prescott G L. Trichotillometry: the reliability and practicality of hairpluckability as a method of nutritional assessment. Nutr J 2007: 6: 9;and Chase E S, Weinsier R L, Laven G T, Krumdieck C L. Trichotillometry:the quantitation of hair pluckability as a method of nutritionalassessment. Am J Clin Nutr 1981: 34(10): 2280-2286.each of which isincorporated herein in its entirety by reference. Other systems tomeasure the strength of the arrector pili muscle can use atrichotillometer or a device used to measure tensile forces. Tractionalopecia is a form of alopecia, or gradual hair loss, caused primarilyby pulling force applied to the hair. Several different hair styles andhair extensions can cause or exacerbate traction alopecia. For example,certain styles or braiding patterns that pull the hairline have beenshown to cause traction alopecia. Particularly tight braids, barrettes,or the installation of hair extensions can exert sufficient chronicforce on the hair follicles to cause traction alopecia. Generally,traction alopecia has a mechanical origin based on the force on thehair. For example, chronic pulling on the hair follicles can causeinflammation. Eventually, follicular scarring and permanent alopecia canoccur from prolonged pulling.

Accordingly, the mechanical strain of the pulling force on the rootcauses the damage to the follicle in the root. Additionally, asillustrated in FIGS. 1A-1B, each follicular unit contains a smoothmuscle anchoring the hair to the epidermis. When the smooth muscle isrelaxed as illustrated in FIG. 1A, the muscle does not supply muchrestraining force and the follicle can be removed easily. When thesmooth muscle or arrector pili (AP) contracts as illustrated in FIG. 1B,the follicle stands up and is restrained by additional force from thesmooth muscle rather than just primarily the surrounding connectivetissue of the dermis. Accordingly, the smooth muscle can provide moreretention force in opposition to a force that would pull on the hair todislodge the follicle if it is contracted. Thus, by contracting thearrector pili (AP) muscle, the root can be more firmly grounded into thedermis of the skin preventing the mechanical strain from damaging theroot and dermis, i.e. requiring a larger epilation force for removal ofthe hair follicle. This would prevent the chronic stressing from pullingof the hair observed in different hairstyles from doing as much damageto the root, and thereby would prevent or reduce the risk of developingtraction alopecia.

In some aspects, then, the technology described herein relates to thereduction of the force exerted on the root of a hair. In practice, this“reduction” in force is more akin to providing a better balancing forceagainst a traction on the hair itself—that is, the treatments describedherein will not necessarily reduce the amount of traction on the hair,but by stimulating the contraction of the arrector pili muscles, thetreatments provide a force that at least partially counters the effectof the traction or pulling force, thereby protecting the root againstthe epilatory effect of the traction.

Accordingly, disclosed herein are methods for contracting the smoothmuscle cells or arrector pili while a patient is wearing a hairextension, wig, a tightly woven or pulling hairstyle, combing theirhair, or engaging in other behavior that pulls back on the follicles ofthe hair. Several methods are disclosed for contracting the AP muscleincluding application of a pharmaceutical composition containing an A1ARagonist, a muscarinic receptor agonist, a nicotinic receptor agonist,and/or a cholinesterase inhibitor, electrical stimulation of the hairfollicles and others.

Disorders to be Treated or Prevented

Applicants disclose herein methods to treat or prevent variousconditions related to mechanical stress on the human hair. In oneembodiment, the invention concerns treating, reducing or preventing hairloss from disorders such as traction alopecia, androgenic alopecia (alsoknown as androgenetic alopecia), alopecia areata, and alopeciauniversalis, and hair loss due to hair brushing, combing, etc.comprising topical administration to a person in need thereof of atherapeutically effective amount of an A1AR agonist, a muscarinicreceptor agonist, a nicotinic receptor agonist, and/or a cholinesteraseinhibitor, or of any of the active agents described herein. In anotherembodiment, the invention concerns a method for the reduction of theforce exerted on a root of a hair comprising topical administration to aperson in need thereof of a therapeutically effective amount of an A1ARagonist, a muscarinic receptor agonist, a nicotinic receptor agonist,and/or a cholinesterase inhibitor, or of any of the active agentsdescribed herein. In another embodiment, the invention concerns a methodfor increasing hair epilation force comprising topical administration toa person in need thereof of a therapeutically effective amount of anA1AR agonist, a muscarinic receptor agonist, a nicotinic receptoragonist, and/or a cholinesterase inhibitor, or of any of the activeagents described herein. In another embodiment, the invention concerns acosmetic method for piloerecting hair or raising hair comprising topicaladministration to a person in need thereof of a therapeuticallyeffective amount of an A1AR agonist, a muscarinic receptor agonist, anicotinic receptor agonist, and/or a cholinesterase inhibitor, or of anyof the active agents described herein.

In one aspect, the therapeutically effective amount of the active agentadministered is a pilomotor effective amount. In one aspect, thetherapeutic or active agent is applied to a skin section, such as asection of the scalp, which contains at least one hair follicle. In afurther embodiment, the at least one hair follicle is under tension.

The active or therapeutic agent may be administered to the hair follicleor scalp to promote contraction of the AP muscle and thereby reduce,treat or prevent alopecia and the other disorders discussed herein. Itis specifically contemplated that the active agent can be administeredto the hair follicle or the scalp in combination with an agent thatretards systemic absorption of the agent across the dermis. In thismanner, agents that might otherwise have unwanted systemic effects canbe used to treat, reduce or prevent alopecia or other disordersdiscussed herein while avoiding such systemic side effects. Oneformulation of agents for topical administration in a manner that avoidssystemic absorption is discussed in detail in U.S. Patent App. Pub.2009/0068287, which is incorporated herein by reference in its entirety.

In another aspect, described herein is a method for prevention oftraction alopecia comprising: applying a therapeutically effectiveamount, such as a pilomotor effective amount, of an A1AR agonist, amuscarinic receptor agonist, a nicotinic receptor agonist, and/or acholinesterase inhibitor, or of any of the active agents describedherein to the scalp to an area with a group of follicles that willexperience a pulling force from a hair augmentation device; andattaching the hair augmentation device to the group of follicles. In oneembodiment, the hair augmentation device is a hair extension orextensions. In another embodiment the hair augmentation device is aweave. In another embodiment, the hair augmentation device is abarrette.

In another aspect, described herein is method of reducing hair shedding,such as occurs during brushing, combing, weaving, flat ironing,showering, curling, wift, attaching hair extensions or wigs, trading,pony tails, or cosmetic procedures, the method comprising applying atherapeutically effective amount, such as a pilomotor effective amount,of an A1AR agonist, a muscarinic receptor agonist, a nicotinic receptoragonist, and/or a cholinesterase inhibitor, or of any of the activeagents described herein topically to a portion of skin that includes atleast one hair follicle. In one embodiment, the A1AR agonist, muscarinicreceptor agonist, nicotinic receptor agonist, and/or cholinesteraseinhibitor, or other active agent described herein is present on a brushor comb that may then be used to administer the therapeutic agent suchas the A1AR agonist, muscarinic receptor agonist, nicotinic receptoragonist, and/or cholinesterase inhibitor, or other active agentdescribed herein. In another embodiment, the active agent is applied tothe skin prior to the brushing or combing.

In another aspect, the cosmetic procedure is selected from the groupconsisting of brushing, braiding, flat ironing, and combinations of twoor more thereof. The therapeutic agent may be topically applied once,twice, or more often per day. In another embodiment, the active agent isapplied to the skin twice daily. In another embodiment, the active agentis applied to the skin prior to the cosmetic procedure.

In another aspect, described herein is a method for treatment oftrichotillomania comprising applying a pilomotor effective amount ofA1AR agonist, a muscarinic receptor agonist, a nicotinic receptoragonist, and/or a cholinesterase inhibitor, or other active agentdescribed herein topically to a portion of skin that includes at leastone hair follicle.

The disclosure also concerns evaluating an individual for susceptibilityto treatment according to the methods disclosed herein. In oneembodiment, the method comprises (1) applying an A1AR agonist, amuscarinic receptor agonist, a nicotinic receptor agonist, or acholinesterase inhibitor, (e.g., without limitation, synephrine), on asite on the skin of a person; and (2) 30 to 60 minutes after applying,observe whether the person's skin shows goose bumps or pilioerection atthe site; wherein if pilioerection or goose bumps are observed,diagnosing the person as likely to be a successful candidate for use ofthe A1AR agonist, muscarinic receptor agonist, nicotinic receptoragonist, or cholinesterase inhibitor for any of the many methods oftreatment or prevention described herein. This method may be combinedwith any of the other methods of treatment or prevention or reduction ofhair loss described herein to provide an initial diagnosis of thosepeople most likely to benefit from the methods described. The step ofapplication to the skin may be, in one embodiment, applying a bandage orpatch coated with the A1AR agonist, muscarinic receptor agonist,nicotinic receptor agonist, or cholinesterase inhibitor to the person'sarm or thigh. In another embodiment of any composition or methodinvolving an A1AR agonist, the agonist is synephrine or phenylephrine.

Active or Therapeutic Agent

Useful active agents (referred to as active agents or therapeutic agentsherein) for the methods of use disclosed herein include agonists ofmuscarinic acetylcholine receptors (mAChRs, also known as muscarinicacetylcholine receptors), agonists of nicotinic acetylcholine receptor(also referred to as nicotinic receptors, nAChRs, or nicotinicacetylcholine receptors), acetylcholine receptor agonists such asneuropeptide-Y, and cholinesterase inhibitors. The agonists may beselective or nonselective agonists of mAChRs or nAChRs. In otherembodiments, a prodrug that is activated to become a mAChR or nAChRagonist or a cholinesterase inhibitor can be utilized. Any of the activeagents disclosed herein may be used in combination with another activeagent disclosed herein, including in combination with another activeagent of the same type (such as without limitation one muscarinicacetylcholine receptor agonist in combination with a second muscarinicacetylcholine receptor agonist) or in combination with a different typeof active agent (such as without limitation a muscarinic acetylcholinereceptor agonist with a nicotinic acetylcholine receptor agonist). By“combination” is meant that the active agents are applied within aboutone hour of each other to the skin, or at substantially the same time tothe skin, or otherwise such that the combined active agents are expectedto show effect on the skin or hair follicles at the same time.

Muscarinic acetylcholine receptors (mAChRs) and nicotinic acetylcholinereceptors (nAChRs) are acetylcholine receptors of an autonomic nervoussystem that can be manipulated by agonists.

mAChRs are found in tissues innervated by postganglionic parasympatheticneurons, in presynaptic noradrenergic and cholinergic nerve terminals,in non-innervated sites in vascular endothelium, and in the centralnervous system. There are subtypes of muscarinic receptors, which aretypically referred to as M_(i) (e.g., M₁, M₂, M₃, M₄, and M₅).Muscarinic receptor agonists that may be used according to the presentcompositions and methods include without limitation NNC 11-1585, NNC11-1607, pentylthio-TZTP, NNC 11-1314, xanomeline, sabcomeline,arecaidine propargyl ester, acetylcholine, arecoline, oxotremorine,McN-A-343, milameline, oxotremorine-M, methylfurmethide, bethanechol,carbachol, furtrethonium, methacholine, aceclidine, pilocarpine, andmuscarine. It has been discovered that at least M₂-type agonists andM₃-type agonists can be used to induce direct smooth muscle contraction.

Suitable M₂ agonists for the compositions and methods of the presentdisclosure include, but are not limited to, methacholine,(2S,2′R,3′S,5′R)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine3-sulfoxide methyl iodide, [³H]oxotremorine-M, NNC 11-1585, NNC 11-1607,pentylthio-TZTP, methacholine, NNC 11-1314, xanomeline, oxotremorine,acetylcholine, arecaidine propargyl ester, carbachol, McN-A-343,arecoline, methylfurmethide, pilocarpine, furtrethonium, bethanechol,iperoxo, aceclidine, [18F]FP-TZTP, and berberine. Suitable M₃ agonistsfor the compositions and methods of the present disclosure include, butare not limited to, NNC 11-1585, NNC 11-1607, pentylthio-TZTP, NNC11-1314, xanomeline, sabcomeline, arecaidine propargyl ester,acetylcholine, arecoline, oxotremorine, McN-A-343, milameline,oxotremorine-M, methylfurmethide, bethanechol, carbachol, furtrethonium,methacholine, aceclidine, L-689,660 (mixed M₁/M₃ agonist), andpilocarpine.

Nicotinic acetylcholine receptors are located in sympathetic andparasympathetic ganglia, in the adrenal medulla, in the neuromuscularjunction of the skeletal muscle, and in the central nervous system.Nicotinic acetylcholine receptors are ligand-gated ion channels whoseactivation results in a rapid increase in cellular permeability tosodium and calcium. They are pentameric arrays of one to four distinctbut homologous subunits, surrounding an internal channel. The α subunit,which has binding sites for ACh, is present in at least two copies.Agonist molecules induce a conformational change that opens the channel.Antagonist molecules may bind to these sites, but do not elicit theconformational change.

There are at least two subtypes of nicotinic receptors, generallyreferred to as N_(M) and N_(N). The N_(M) nicotinic receptor mediatesskeletal muscle stimulation, while the N_(N) nicotinic receptor mediatesstimulation of the ganglia of the autonomic nervous system. Usefulnicotinic receptor agonists to treat conditions and disorders disclosedherein include without limitation: varenicline tartrate, galantaminehydrobromide, nicotine, carbachol, suxamethonium chloride(succinylcholine chloride), and epibatidine.

The muscarinic and nicotinic receptor agonists mimic acetylcholineeffect by stimulating the relevant receptors themselves or by actingthrough the axon reflex. Another way of accomplishing the same thing isto reduce the destruction of acetylcholine (Ach) following its release.This can be achieved by cholinesterase inhibitors, which are also calledthe anticholinesterases. They mimic the effect of combined muscarinicand nicotinic agonists. By inhibiting acetylcholinesterase andpseudocholinesterase, these drugs allow ACh to build up at itsreceptors. Thus, they result in enhancement of both muscarinic andnicotinic agonist effect. Suitable cholinesterase inhibitors for thepresent methods and compositions include without limitationphysostigmine, neostigmine, edrophonium, pyridostigmine, echotihiophate,ambenonium, demecarium, tacrine, donepezil, rivastigmine, galantamine,and pralidoxime. In another embodiment, the active agent useful fortreatment of the disorders and diseases described herein isneuropeptide-Y, which is an acetylcholine receptor agonist. In oneembodiment, the present disclosure concerns one of the methods disclosedherein, comprising applying a therapeutically effective amount of anactive agent selected from the group consisting of neuropeptide-Y,muscarinic acetylcholine receptor agonists, nicotinic acetylcholinereceptor agonists, and cholinesterase inhibitors topically to an area ofthe skin, such as an areas of the scalp, containing a hair follicle.

In another embodiment, the active agent used in the inventive methodsherein is an A1AR agonist. “Alpha-1 adrenergic receptor agonist” or“A1AR agonist” refers to a ligand that binds the alpha-1adrenergicreceptor on smooth muscle cells and activates smooth muscle contraction.In some embodiments, the AIAR agonist is selective for thealpha-1adrenergic receptor. Additionally, the term “alpha-1 adrenergicreceptor agonist” can include agents that when applied will induce therelease of endogenous alpha-1 adrenergic receptor agonists (e.g.epinephrine) that activates smooth muscle contraction or agents thatwhen applied inhibit the “re-uptake” or degradation of endogenousalpha-1adrenergic receptor agonists (e.g. epinephrine) that activatessmooth muscle contraction. In another embodiment, the active agent usedis a “smooth muscle agonist,” which is an agent that promotes or resultsin contraction of the smooth muscle. Thus, an alpha-1adrenergic receptoragonist that promotes or results in smooth muscle contraction is asmooth muscle agonist, but so also are, e.g., an alpha 2 adrenergicreceptor agonist that promotes smooth muscle contraction, agents thatthat induce the release of endogenous alpha 2 adrenergic receptoragonist that results in smooth muscle contraction, and agents thatinhibit the re-uptake or degradation of endogenous alpha 2 adrenergicreceptor agonists that activate smooth muscle contraction. Suitable A1ARagonists for use in the present description include without limitationphenylephrine, phenylephrine pivalate, amediphrine, synephrine,cirazoline, desvenlafaxine, etilfrine, metaraminol, methoxamine,naphazoline, oxymetazoline, pseudoephrine, m-synephrine, p-synephrine,octopamine, hordenine, tetrahydrozoline, isometheptene, metaraminol,nicergoline, ergonovine, levonordefrin, phendimetrazine, methoxamine,midodrine, clonidine, pergolide, xylometazoline, droxidopa, epinephrine,mephentermine, 4-methoxyamphetamine, benzphetamine, naphazoline,apraclondine, bromocriptine, oxymetazoline, phenylpropanolamine,pseudoephedrine, dipivefrin, noradrenaline, chloroethylclonidine,norepinephrine, A61603, NS-49, [¹²⁵I]HEAT, noradrenaline, adrenaline,clonidine, St 587, SKF 89748, 6-fluoro-noradrenaline,methylnoradrenaline, inanidine, NS-49, amidephrine, and dabuzalgron anddopamine. In certain embodiments, the A1AR agonist is synephrine, or isselected from phenylephrine, synephrine, oxymetazoline, and methoxamine.In one embodiment, the therapeutic agent is norepinephrine. Anothersuitable therapeutic agent for use in the inventive methods herein isextract of Bitter orange (Citrus aurantium), which contains synephrinealkaloids and para-octopamine. See Satoh, Y., Tashiro, S., Satoh, M.,Fujimoto, Y., Xu, J. Y., and Ikekawa, T. [Studies on the bioactiveconstituents of Aurantii Fructus Immaturus]. Yakugaku Zasshi1996;116(3):244-250. Additionally, derivatives of A1AR agonists can beutilized including derivatives of the compounds mentioned above. Inother embodiments, a prodrug that is activated to become an A1AR agonistcan be utilized. For example, midodrine is one such prodrug. Aparticular prodrug can be activated by endogenous enzymes in the scalpsuch as Caspase-1 when follicular inflammation is present, e.g., at thelocation of application of a hair extension. In one embodiment, the A1ARagonist is synephrine. In one embodiment, the A1AR agonist isphenylephrine or synephrine, including compositions comprising the1-enantiomer of synephrine, which isR-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol, that are essentiallyfree of other enantiomers of synephrine, or in which less than 30%, 25%,20%, 15%, 10%, 12%, 5%, 3%, 1%, or 0.5% by weight of the synephrinepresent in the composition is a different enantiomer. The synephrineenantiomer R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol may beobtained from natural bitter orange extract. In one embodiment, thetherapeutic agent is derived from bitter orange, Citrusaurantium, or isan extract of bitter orange, such as a bitter orange extract thatcontains 95%, 96%, 97%, 98%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, or 2% by weight or from 5-10%, 10-15%,5-1YYo, 20-25%, 15-20%, 25-30%, 30-35%, 35-40%, 40-45%, 45-55%, 50-60%,60-70%, 70-80%, 80-90%, 85-95%, or 90-99% of one enantiomer ofsynephrine, R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol. Extracts ofbitter orange contain high levels of only one synephrine enantiomer,namely, R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol, and arepreferred for use in the present methods and compositions of thedisclosure.

Additionally, derivatives of alpha-ladrenergic receptor agonists,muscarinic acetylcholine receptor agonists, nicotinic acetylcholinereceptor agonists, or cholinesterase inhibitors can be utilizedincluding derivatives of the compounds mentioned above. In otherembodiments, a prodrug that is activated to become an A1AR agonist,muscarinic acetylcholine receptor agonist, nicotinic acetylcholinereceptor agonist, or cholinesterase inhibitor can be utilized.Midodrine, phenylephrine oxazolidine, and phenylephrine pivalate areexamples of three such prodrugs. Phenylephrine pivalate is an A1ARagonist in addition to being a prodrug of phenylephrine. A particularprodrug can be activated by endogenous enzymes in the skin such asCaspase-1. Another embodiment is a method comprising applying atherapeutically effective amount of an alpha-ladrenergic receptorantagonist or a beta adrenergic receptor agonist to the skin or scalp totreat an overdose of alpha-ladrenergic receptor agonist.

As used herein, a “prodrug” refers to compounds that can be convertedvia some chemical or physiological process (e.g., enzymatic processesand metabolic hydrolysis) to an active agent. Thus, the term “prodrug”also refers to a precursor of a biologically active compound that ispharmaceutically acceptable. A prodrug may be inactive when administeredto a subject, i.e. an ester, but is converted in vivo to an activecompound, for example, by hydrolysis to the free carboxylic acid or freehydroxyl. The prodrug compound often offers advantages of solubility,tissue compatibility or delayed release in an organism. The term“prodrug” is also meant to include any covalently bonded carriers, whichrelease the active compound in vivo when such prodrug is administered toa subject. Prodrugs of an active compound may be prepared by modifyingfunctional groups present in the active compound in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent active compound. Prodrugs include compounds wherein ahydroxy, amino or mercapto group is bonded to any group that, when theprodrug of the active compound is administered to a subject, cleaves toform a free hydroxy, free amino or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, acetate, formateand benzoate derivatives of an alcohol or acetamide, formamide andbenzamide derivatives of an amine functional group in the activecompound and the like. See Harper, “Drug Latentiation” in Jucker, ed.Progress in Drug Research 4:221-294 (1962); Morozowich et al,“Application of Physical Organic Principles to Prodrug Design” in E. B.Roche ed. Design of Biopharmaceutical Properties through Prodrugs andAnalogs, APHA Acad. Pharm. Sci. 40 (1977); Bioreversible Carriers inDrug in Drug Design, Theory and Application, E. B. Roche, ed., APHAAcad. Pharm. Sci. (1987); Design of Prodrugs, H. Bundgaard, Elsevier(1985); Wang et al. “Prodrug approaches to the improved delivery ofpeptide drug” in Curr. Pharm. Design. 5(4):265-287 (1999); Pauletti etal. (1997) Improvement in peptide bioavailability: Peptidomimetics andProdrug Strategies, Adv. Drug. Delivery Rev. 27:235-256; Mizen et al.(1998) “The Use of Esters as Prodrugs for Oral Delivery of (3-Lactamantibiotics,” Pharm. Biotech. 11:345-365; Gaignault et al. (1996)“Designing Prodrugs and Bioprecursors I. Carrier Prodrugs,” Pract. Med.Chem. 671-696; Asgharnejad, “Improving Oral Drug Transport”, inTransport Processes in Pharmaceutical Systems, G. L. Amidon, P. I. Leeand E. M. Topp, Eds., Marcell Dekker, p. 185-218 (2000); Balant et al.,“Prodrugs for the improvement of drug absorption via different routes ofadministration”, Eur. J. Drug Metab. Pharmacokinet., 15(2): 143-53(1990); Balimane and Sinko, “Involvement of multiple transporters in theoral absorption of nucleoside analogues”, Adv. Drug Delivery Rev.,39(1-3): 183-209 (1999); Browne, “Fosphenytoin (Cerebyx)”, Clin.Neuropharmacol. 20(1): 1-12 (1997); Bundgaard, “Bioreversiblederivatization of drugs—principle and applicability to improve thetherapeutic effects of drugs,” Arch. Pharm. Chemi 86(1): 1-39 (1979);Bundgaard H. “Improved drug delivery by the prodrug approach,”Controlled Drug Delivery 17: 179-96 (1987); Bundgaard H. “Prodrugs as ameans to improve the delivery of peptide drugs,” Arfv. Drug DeliveryRev. 8(1): 1-38 (1992); Fleisher et al. “Improved oral drug delivery:solubility limitations overcome by the use of prodrugs,” Arfv. DrugDelivery Rev. 19(2): 115-130 (1996); Fleisher et al. “Design of prodrugsfor improved gastrointestinal absorption by intestinal enzymetargeting,” Methods Enzymol. 112 (Drug Enzyme Targeting, Pt. A): 360-81,(1985); Farquhar D, et al., “Biologically ReversiblePhosphate-Protective Groups,” Pharm. Sci., 72(3): 324-325 (1983);Freeman S, et al., “Bioreversible Protection for the Phospho Group:Chemical Stability and Bioactivation of Di(4-acetoxy-benzyl)Methylphosphonate with Carboxyesterase,” Chem. Soc., Chem. Commun.,875-877 (1991); Friis and Bundgaard, “Prodrugs of phosphates andphosphonates: Novel lipophilic alphaacyloxyalkyl ester derivatives ofphosphate- or phosphonate containing drugs masking the negative chargesof these groups,” Eur. J. Pharm. Sci. 4: 49-59 (1996); Gangwar et al.,“Pro-drug, molecular structure and percutaneous delivery,” Des.Biopharm. Prop. Prodrugs Analogs, [Symp.] Meeting Date 1976, 409-21.(1977); Nathwani and Wood, “Penicillins: a current review of theirclinical pharmacology and therapeutic use,” Drugs 45(6): 866-94 (1993);Sinhababu and Thakker, “Prodrugs of anticancer agents,” Adv. DrugDelivery Rev. 19(2): 241-273 (1996); Stella et al., “Prodrugs. Do theyhave advantages in clinical practice?” Drugs 29(5): 455-73 (1985); Tanet al. “Development and optimization of anti-HIV nucleoside analogs andprodrugs: A review of their cellular pharmacology, structure-activityrelationships and pharmacokinetics,” Adv. Drug Delivery Rev. 39(1-3):117-151 (1999); Taylor, “Improved passive oral drug delivery viaprodrugs,” Adv. Drug Delivery Rev., 19(2): 131-148 (1996); Valentino andBorchardt, “Prodrug strategies to enhance the intestinal absorption ofpeptides,” Drug Discovery Today 2(4): 148-155 (1997); Wiebe and Knaus,“Concepts for the design of anti-HIV nucleoside prodrugs for treatingcephalic HIV infection,” Adv. Drug Delivery Rev.: 39(1-3):63-80 (1999);Waller et al., “Prodrugs,” Br. J. Clin. Pharmac. 28: 497-507 (1989),which are incorporated by reference herein in their entireties.

Formulations

The therapeutic agents, particularly the A1AR agonist, muscarinicreceptor agonist, nicotinic receptor agonist, and cholinesteraseinhibitor, described herein and used in the present methods may beformulated into compositions according to the knowledge of one of skillin the art. In one embodiment, the therapeutic agent is formulated fortopical slow or prolonged release. As but one example, in one embodimentthe AP stimulating agent is encapsulated for slow release and integratedinto a hair extension.

In another embodiment, the therapeutic agent is formulated in a shampoo(which can reduce hair shedding during hair brushing), a foam, ointment,spray, solution, gel, slow release capsule, oral tablet, or any similarcompound or delivery vehicle or methodology. Topical application ispreferred. In one embodiment, the composition is formulated in a topicalcream. In another embodiment, the composition is formulated in a hairstyling product selected from the group consisting of a styling gel, astyling foam, and a hair conditioner.

In another embodiment, the composition may comprise an exfoliating agentto promote abrasion of the surface of the scalp. Examples of theexfoliating agent include (1) inorganic and/or metallic particles suchas: boron nitride, in body-centered cubic form (Borazon®);aluminosilicate (e.g. nepheline); zircon; mixed oxides of aluminum suchas emery; zinc oxide; aluminum oxides such as aluminas or corundum;titanium oxide; titanium oxide coated mica; carbides, in particularsilicon carbide (carborundum); or other metal oxides; metals, and metalalloys such as iron shot, steel shot, and in particular perlite;silicates such as glass, quartz, sand, or vermiculite; calcium carbonate(e.g. Bora-Bora sand or Rose de Brignoles sand) or magnesium carbonate;sodium chloride; pumice stone; amorphous silica; diamond; ceramics, and(2) organic particles such as: fruit stones, in particular apricotstones, e.g. Scrubami® apricot; wood cellulose, e.g. ground bamboo stem;coconut shell, e.g. coconut exfoliator; polyamides, in particularNylon-6; sugars; plastic microbeads, e.g. polyethylenes orpolypropylenes; ground walnut; ground apricot seed; ground shells, and(3) mixed particles associating organic and inorganic compounds, andparticles coated in the above compounds. The exfoliating agents may bein the form of microbeads of less than five millimeters in its largestdimension that have an exfoliating effect.

In one embodiment, the composition comprising an A1AR agonist, amuscarinic receptor agonist, a nicotinic receptor agonist, and/or acholinesterase inhibitor can be formulated as a drug. In one embodiment,the composition comprising an A1AR agonist, a muscarinic receptoragonist, a nicotinic receptor agonist, and/or a cholinesterase inhibitorcan be formulated as a cosmetic product.

In another embodiment, the AP muscle can be contracted via electricalstimulation to the scalp. The stimulation can be controlled by a batteryand control unit embedded into a hair extension, or in, e.g., a hairbrush or comb. The control unit can contain an accelerometer to detectthe optimal time to contract the AP muscles based on the posture of thesubject or the subject's hair.

The amount of therapeutic agent present in the composition may bedetermined by one of skill in the art using known methodologies. Incertain embodiments, the A1AR agonist or other stimulator of AP musclecontraction, such as a muscarinic receptor agonist, a nicotinic receptoragonist, and/or a cholinesterase inhibitor, is present in thecomposition in a concentration from about 0.20% to 0.30%, or about 0.25%by weight. In another embodiment, the therapeutic agent such as an A1ARagonist, a muscarinic receptor agonist, a nicotinic receptor agonist,and/or a cholinesterase inhibitor is present in the composition in aconcentration of about 0.25%, 0.33%, 0.5%, 1%, 2%, 2.5%, or 10% byweight.

In other embodiments, the therapeutic agent, such as an A1AR agonist, amuscarinic receptor agonist, a nicotinic receptor agonist, and/or acholinesterase inhibitor, is present in the topical composition for usein the methods disclosed herein in a concentration from about 0.1% to35%, about 1.0% to 30%, about 0.2% to 30%, about 0.2% to 25%, about 0.2%to 20%, about 0.2% to 15%, about 0.2% to 10%, about 0.2% to 5%, about0.2% to 4%, about 0.2% to 3%, about 0.2% to 2%, about 0.2% to 1%, about10.0% to 30%, about 15.0% to 30%, about 20.0% to 30%, about 10% to 20%,about 10% to 15%, about 15% to 20%, about 15% to 60%, about 20% to 60%,about 50% to 60%, and about 45% to 55% by weight. For certaintherapeutic agents, such as synephrine (racemic mixture), aconcentration of about 25% to 60%, 30% to 50%, 30% to 60%, 25% to30%,40% to 50%, or 50% to 55% by weight of the total weight of thecomposition is desirable.

In one embodiment, the composition comprises an A1AR agonist, amuscarinic receptor agonist, a nicotinic receptor agonist, and/or acholinesterase inhibitor in a concentration of about 0.25%, about 0.33%,about 0.5%, about 1%, about 2%, about 2.5%, about 3.0%, about 4.0%,about 10%, about 15%, about 20%, or about 25% by weight.

The compositions used in the present disclosure, particularlycompositions containing an A1AR agonist, a muscarinic receptor agonist,a nicotinic receptor agonist, and/or a cholinesterase inhibitor, may beformulated with a preservative such as EDTA (0.1-0.5% by weight of theformulation) and/or sodium metabisulfite (0.1-0.5% by weight of theformulation). In some embodiments, the composition includes apenetration enhancer, such as a penetration enhancer selected from oneor more of the group consisting of alcohols, glycols, fatty acids, fattyesters, fatty ethers, occlusive agents, surface active agents,dimethylaminopropionic acid derivatives, terpenes, sulfoxides, cyclicethers, amides, and amines. Other components of the formulations usedherein may be chosen from cosmetically approved excipients known in theart, including water, thickeners, etc.

The composition may be packaged in a kit with an applicator forapplication to the skin. The invention is also directed to a kitcomprising a composition of the therapeutic agent and an applicator, andto a kit comprising a composition of the therapeutic agent and a hairbush or comb, particularly a brush or comb that provides exfoliatingeffect on the scalp such that there is light abrasion after its use thatenhances penetration of the therapeutic agent to the AP muscle. In oneembodiment, the therapeutic agent is provided in a metered doseapplicator that provides for a fixed volume of the composition to beadministered with each administration, such as 1 ml of the topicalcomposition per administration.

It will be understood that the ranges described above, and throughoutthis document, are also intended to encompass single values containedwithin these ranges. For example, for a formulation comprising aparticular ingredient in a range between 1-50%, a percentage of 5% or49% is also intended to be disclosed.

In one embodiment, the compositions of the present invention contain10%,11%,12%,13%,14%,15%,16%,17%,18%,19%,20%,21%,22%, 23%, 24%, 25%, 16%,27%, 28%, 29%, 30% or 31% by weight of bitter orange extract, such as anextract that contains 3-5%, 5-10%, 6%, 9%, 10-15%, 15-20%, 20-40%,40-60%, 60-80%, or 80-95% synephrine, or the composition contains fromabout 5-10%, 10-15%, 15-20%, 25-30% or 30-40% by weight of bitter orangeextract, such as an extract containing from about 3-5%, 5-10%, 6%, 9%,10-15%, 15-20%,20-30%, 30-50%, 50-60%, 60-70%,70-80%, 80-90% or 80-99%synephrine. In a preferred embodiment, the compositions of the presentinvention contain 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%,21%,22%,23%,24%,25%, 16%,27%,28%,29%,30% or 31% by weight of a bitterorange extract, wherein the extract contains 50-90%, 50-60%, 60-70%,70-80%, 80-90%, 85-95% or 90-99% synephrine and substantially all of thesynephrine in the extract is the enantiomerR(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol.

In one embodiment, the A1AR agonist is phenylephrine, or apharmaceutically acceptable salt or hydrate thereof, in a composition ina concentration of 0.25% to 40%, 0.25% to 25% by weight, or 0.5% to22.5% by weight, or 0.75% to 20% by weight, or 1% to 17.5% by weight, or1.5% to 15% by weight, or 2% to 14.5% by weight, or 2.5% to 14% byweight, or 5% to 13.5% by weight, or 7.5% to 12.5% by weight, or 8% to12% by weight, or 8.5% to 11.5% by weight, or 9% to 11% by weight, or9.25% to 10.75% by weight, or 9.5% to 10.5% by weight, or 9.6% to 10.4%by weight, or 9.7% to 10.3% by weight, or 9.8% to 10.2% by weight, or9.9% to 10.1% by weight, or 9.95% to 10.05% by weight, or 9.96% to10.04% by weight, or 9.97% to 10.03% by weight, or 9.98% to 10.02% byweight, or 9.99% to 10.01% by weight.

In one embodiment, the A1AR agonist is phenylephrine, or apharmaceutically acceptable salt or hydrate thereof, in a composition ina concentration at a range of 0.25%, 0.5%, 0.75%, 1%, 1.5%, 2%, 2.5%,5%, 7.5%, 8%, 8.5%, 9%, 9.25%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, 9.95%,9.96%, 9.97%, 9.98%, or 9.99% by weight as the lower weight limit of therange to an upper weight limit of 10.01%, 10.02%, 10.03%, 10.04%,10.05%, 10.1%, 10.2%, 10.3%, 10.4%, 10.5%, 10.75%, 11%, 11.5%, 12%,12.5%, 13.5%, 14%, 14.5%, 15%, 17.5%, 20%, 22.5%, 25%,30%,35%,40%,45%,or 50% by weight (e.g., a range of0.25% to 10.01%, 0.25% to 10.02%, 0.5%to 10.01%, 0.5% to 10.02%, etc.).

In one embodiment, the A1AR agonist is phenylephrine, or apharmaceutically acceptable salt or hydrate thereof, in a composition ina concentration of 0.25% by weight, or 0.5% by weight, or 0.75% byweight, or 1% by weight, or 1.5% by weight, or 2% by weight, or 2.5% byweight, or 5% by weight, or 7.5% by weight, or 8% by weight, or 8.5% byweight, or 9% by weight, or 9.25% by weight, or 9.5% by weight, or 9.6%by weight, or 9.7% by weight, or 9.8% by weight, or 9.9% by weight, or9.95% by weight, or 9.96% by weight, or 9.97% by weight, or 9.98% byweight, or 9.99% by weight, or 10% by weight, or 10.01% by weight, or10.02% by weight, or 10.03% by weight, or 10.04% by weight, or 10.05% byweight, or 10.1% by weight, or 10.2% by weight, or 10.3% by weight, or10.4% by weight, or 10.5% by weight, or 10.75% by weight, or 11% byweight, or 11.5% by weight, or 12% by weight, or 12.5% by weight, or13.5% by weight, or 14% by weight, or 14.5% by weight, or 15% by weight,or 17.5% by weight, or 20% by weight, or 22.5% by weight, or 25% byweight, or 30% by weight, or 40% by weight, or 45% by weight, or 50% byweight, or 55% by weight.

In another embodiment, the composition comprises an A1AR agonist that issynephrine, or a pharmaceutically acceptable salt or hydrate thereof, orthat comprises one enantiomer of synephrine, namelyR-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol and is substantially freeof other enantiomer(s) of synephrine or has less than 30%, 25%, 20%,15%, 10%, 12%, 5%, 3%, 1%, or 0.5% by weight of the synephrine presentin the composition as a different enantiomer, wherein the synephrine ispresent in the composition in a concentration of 30% to 70% by weight,or 35% to 65% by weight, or 37.5% to 62.5% by weight, or 40% to 60% byweight, or 42.5% to 57.5% by weight, or 45% to 55% by weight, or 45.5%to 54.5% by weight, or 46% to 54% by weight, or 46.5% to 53.5% byweight, or 4 7% to 53% by weight, or 47.5% to 52.5% by weight, or 48% to52% by weight, or 48.25% to 51.75% by weight, or 48.5% to 51.5% byweight, or 48.75% to 51.25% by weight, or 49% to 51% by weight, or49.25% to 50.75% by weight, or 49.5% to 50.5% by weight, or 49.6% to50.4% by weight, or 49.7% to 50.3% by weight, or 49.8% to 50.2% byweight, or 49.9% to 50.1% by weight.

In another embodiment, the composition comprises an A1AR agonist that issynephrine, or a pharmaceutically acceptable salt or hydrate thereof, orthat comprises one enantiomer of synephrine, namelyR-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol and is substantially freeof other enantiomer(s) of synephrine or has less than 30%, 25%, 20%,15%, 10%, 12%, 5%, 3%, 1%, or 0.5% by weight of the synephrine presentin the composition as a different enantiomer, wherein the synephrine ispresent in the composition in a concentration of 20% by weight, or 25%by weight, or 30% by weight, or 35% by weight, or 37.5% by weight, or40% by weight, or 42.5% by weight, or 45% by weight, or 45.5% by weight,or 46% by weight, or 46.5% by weight, or 47% by weight, or 47.5% byweight, or 48% by weight, or 48.25% by weight, or 48.5% by weight, or48.75% by weight, or 49% by weight, or 49.25% by weight, or 49.5% byweight, or 49.6% by weight, or 49.7% by weight, or 49.8% by weight, or49.9% by weight to 50.1% by weight, or 50.2% by weight, or 50.3% byweight, or 50.4% by weight, or 50.5% by weight, or 50.75% by weight, or51% by weight, or 51.25% by weight, or 51.5% by weight, or 51.75% byweight, or 52% by weight, or 52.5% by weight, or 53% by weight, or 53.5%by weight, or 54% by weight, or 54.5% by weight, or 55% by weight, or57.5% by weight, or 60% by weight, or 62.5% by weight, or 65% by weight,or 70% by weight.

In one embodiment, the composition comprises an A1AR agonist that isR-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol substantially free of theother enantiomer of synephrine (or having less than 25%, 20%, 15%, 10%,5%, 1% or 0.1% of the other enantiomer of synephrine) or apharmaceutically acceptable salt or hydrate thereof, in a composition ina concentration of 20% by weight, or 21% by weight, or 25% by weight, or26% by weight, or 30% by weight, or 35% by weight, or 37.5% by weight,or 40% by weight, or 42.5% by weight, or 45% by weight, or 45.5% byweight, or 46% by weight, or 46.5% by weight, or 47% by weight, or 47.5%by weight, or 48% by weight, or 48.25% by weight, or 48.5% by weight, or48.75% by weight, or 49% by weight, or 49.25% by weight, or 49.5% byweight, or 49.6% by weight, or 49.7% by weight, or 49.8% by weight, or49.9% by weight, or 50% by weight, or 50.1% by weight, or 50.2% byweight, or 50.3% by weight, or 50.4% by weight, or 50.5% by weight, or50.75% by weight, or 51% by weight, or 51.25% by weight, or 51.5% byweight, or 51.75% by weight, or 52% by weight, or 52.5% by weight, or53% by weight, or 53.5% by weight, or 54% by weight, or 54.5% by weight,or 55% by weight, or 57.5% by weight, or 60% by weight, or 62.5% byweight, or 65% by weight, or 70% by weight.

In another embodiment, the composition comprises an A1AR agonist that issynephrine, or a pharmaceutically acceptable salt or hydrate thereof, orthat comprises one enantiomer of synephrine, namelyR-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol and is substantially freeof other enantiomer(s) of synephrine or has less than 30%, 25%, 20%,15%, 10%, 12%, 5%, 3%, 1%, or 0.5% by weight of the synephrine presentin the composition as a different enantiomer, wherein the synephrine ispresent in the composition in a concentration of 10% to 60% by weight,or 12.5% to 50% by weight, or 10% to 50% by weight, or 15% to 40% byweight, or 20% to 30% by weight, or 20% to 40% by weight, or 17.5% to30% by weight, or 20% to 25% by weight, or 20.5% to 24.5% by weight, or21% to 24% by weight, or 21.5% to 23.5% by weight, or 21.75% to 23.25%by weight, or 22% to 23% by weight, or 22.1% to 22.9% by weight, or22.2% to 22.8% by weight, or 22.3% to 22.7% by weight, or 22.4% to 22.6%by weight.

In another embodiment, the composition comprises an A1AR agonist that issynephrine, or a pharmaceutically acceptable salt or hydrate thereof, orthat comprises one enantiomer of synephrine, namelyR-0-4-[1-hydroxy-2-(methylamino)ethyl)phenol and is substantially freeof other enantiomer(s) of synephrine or has less than 30%, 25%, 20%,15%, 10%, 12%, 5%, 3%, 1%, or 0.5% by weight of the synephrine presentin the composition as a different enantiomer, wherein the synephrine ispresent in the composition in a concentration of 10% by weight, or 12.5%by weight, or 15% by weight, or 17.5% by weight, or 20% by weight, or20.5% by weight, or 21% by weight, or 21.5% by weight, or 21.75% byweight, or 22% by weight, or 22.1% by weight, or 22.2% by weight, or22.3% by weight, or 22.4% by weight to 22.6% by weight, or 22.7% byweight, or 22.8% by weight, or 22.9% by weight, or 23% by weight, or23.25% by weight, or 23.5% by weight, or 24% by weight, or 24.5% byweight, or 25% by weight, or 30% by weight, or 40% by weight, or 50% byweight, or 60% by weight.

In one embodiment, the composition comprises one enantiomer ofsynephrine, namely R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phcnol, andis substantially free of other enantiomer(s) of synephrine or has lessthan 30%, 25%, 20%, 15%, 10%, 12%, 5%, 3%, 1%, or 0.5% by weight of thesynephrine present in the composition as a different enantiomer, whereinthe R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol is present in thecomposition in a concentration of 20% to 25% by weight.

In a further embodiment, the A1AR agonist is oxymetazoline, or apharmaceutically acceptable salt or hydrate thereof, in a composition ina concentration of 0.01% to 2% by weight, or 0.02% to 1.75% by weight,or 0.03% to 1.5% by weight, or 0.04% to 1.25% by weight, or 0.05% to 1%by weight, or 0.1% to 0.9% by weight, or 0.15% to 0.85% by weight, or0.2% to 0.8% by weight, or 0.25% to 0.75% by weight, or 0.3% to 0.7% byweight, or 0.35% to 0.65% by weight, or 0.4% to 0.6% by weight, or 0.41%to 0.59% by weight, or 0.42% to 0.58% by weight, or 0.43% to 0.57% byweight, or 0.44% to 0.56% by weight, or 0.45% to 0.55% by weight, or0.46% to 0.54% by weight, or 0.47% to 0.53% by weight, or 0.48% to 0.52%by weight, or 0.49% to 0.51% by weight.

In a further embodiment, the A1AR agonist is oxymetazoline, or apharmaceutically acceptable salt or hydrate thereof, in a composition ina concentration of 0.01% by weight, or 0.02% by weight, or 0.03% byweight, or 0.04% by weight, or 0.05% by weight, or 0.1% by weight, or0.15% by weight, or 0.2% by weight, or 0.25% by weight, or 0.3% byweight, or 0.35% by weight, or 0.4% by weight, or 0.41% by weight, or0.42% by weight, or 0.43% by weight, or 0.44% by weight, or 0.45% byweight, or 0.46% by weight, or 0.47% by weight, or 0.48% by weight, or0.49% by weight to 0.51% by weight, or 0.52% by weight, or 0.53% byweight, or 0.54% by weight, or 0.55% by weight, or 0.56% by weight, or0.57% by weight, or 0.58% by weight, or 0.59% by weight, or 0.6% byweight, or 0.65% by weight, or 0.7% by weight, or 0.75% by weight, or0.8% by weight, or 0.85% by weight, or 0.9% by weight, or 1% by weight,or 1.25% by weight, or 1.5% by weight, or 1.75% by weight, or 2% byweight.

In a further embodiment, the Al ARA is oxymetazoline, or apharmaceutically acceptable salt or hydrate thereof, in a composition ina concentration of 0.01% by weight, or 0.02% by weight, or 0.03% byweight, or 0.04% by weight, or 0.05% by weight, or 0.1% by weight, or0.15% by weight, or 0.2% by weight, or 0.25% by weight, or 0.3% byweight, or 0.35% by weight, or 0.4% by weight, or 0.41% by weight, or0.42% by weight, or 0.43% by weight, or 0.44% by weight, or 0.45% byweight, or 0.46% by weight, or 0.47% by weight, or 0.48% by weight, or0.49% by weight, or 0.5% by weight, or 0.51% by weight, or 0.52% byweight, or 0.53% by weight, or 0.54% by weight, or 0.55% by weight, or0.56% by weight, or 0.57% by weight, or 0.58% by weight, or 0.59% byweight, or 0.6% by weight, or 0.65% by weight, or 0.7% by weight, or0.75% by weight, or 0.8% by weight, or 0.85% by weight, or 0.9% byweight, or 1% by weight, or 1.25% by weight, or 1.5% by weight, or 1.75%by weight, or 2% by weight.

In some embodiments, provided herein is an active agent formulated witha carrier or delivery vehicle optimized for delivery of the active agentto the scalp. An A1AR agonist, a muscarinic receptor agonist, anicotinic receptor agonist, and/or a cholinesterase inhibitor can bereleased using several different formulations or release methodsincluding time release, creams, ointments, sprays, capsules, or otherrelease methods. For instance the active agent can be incorporated intoa shampoo for utilization during showering so that when a user brusheshis or her hair, the follicles will be tightly held by the AP muscles toprevent brushing from unnecessarily pulling out healthy hair. In otherembodiments, the active agent can be included in ointments or othertopical creams that could be applied to the scalp so that it can beslowly absorbed into the skin and stimulate the smooth muscle. In otherembodiments, the active agent can be included in a liquid spray oraerosol medium to be applied to the scalp. In other embodiments, theactive agent can be incorporated into capsules or other slow releasevehicles that would allow the chemical or agent to be slowly releasedinto the dermis of the scalp. Capsules or vehicles that encapsulate theactive agent can include, but are not limited to, liposomes, non-ionicliposomes, niosomes, novasome I, erythromycin-Zn complex, microspheres,nanoparticles, solid lipid nanoparticles, and nanoemulsions. In someembodiments, this can include a gel or foam that is applied to thescalp. It is specifically contemplated that the active agent can beformulated in hair care products such as styling gel, styling foam, hairconditioner, hair serum, a hair mask, etc.

Any of the active agents described herein can be applied by a userbefore the application of a hair extension device or other device orcondition that exerts force on the hair follicle. Alternatively, anactive agent can be used routinely (e.g. twice daily) after such adevice has been installed. Routine use of an active agent would beindicated as a prophylactic against traction alopecia for users of ahair extension device or other device that exerts force on the hairfollicle.

Creams or other formulations with different A1AR agonists, muscarinicreceptor agonists, nicotinic receptor agonists, and/or cholinesteraseinhibitors can be applied prior to a user utilizing a hair piece orbrushing the hair. In some embodiments, a hair piece or hair extensionscan contain pads or other absorbent material that can absorb the activeagent in a foam or cream applied prior to application to a user's head.In other embodiments, slow release capsules can be incorporated into thehair extensions or hair pieces, or can be included in barrettes. In someembodiments, barrettes will include pads with an absorbent layer forapplication of the active agent-containing cream or other topicalformulation.

Efficacy of treatment to treat or prevent traction alopecia can bedetermined by monitoring the density of hairs on a given area of thesubject's body, e.g., a given area of the scalp. If the rate of hairloss is reduced, e.g., by 10% or more following treatment, the treatmentis effective for the prevention of traction alopecia. Similarly, if hairdensity remains the same, despite ongoing traction that would normallyhave been expected to cause traction alopecia, the treatment iseffective for the prevention of traction alopecia. If the density ofhair increases, e.g., by 5% or more, e.g., by 10% or more followingtreatment and despite ongoing traction, the treatment is also consideredeffective for the treatment and/or prevention of traction alopecia.

As noted above, it is contemplated that all forms of alopecia canbenefit from the technology described herein. For example, thetechnology described herein can be applicable to prevent or treatandrogenic alopecia. The AP muscle degenerates in the process ofandrogenic alopecia (reviewed, e.g., in Torkamani et al., Int. J.Trichology 6:88-94 (2014)); without wishing to be bound by theory, it iscontemplated that regular stimulation of AP muscle contraction may slowor reduce the loss of the muscle and thereby benefit the treatment orprevention of androgenic alopecia.

It is also contemplated that the technology described herein can bebroadly applicable to any type of condition of which at least one hairfollicle is under tension. Using the active agents that stimulate APmuscle contraction as described herein, it is contemplated that one canlimit or reduce hair shedding under such conditions.

In one aspect, the condition of which at least one hair follicle isunder tension is brushing or combing. Accordingly, the technologydescribed herein relates to a method of reducing hair shedding duringbrushing or combing. As used herein, the term “reducing hair shedding”means that the amount of hair shedding from a subject is reduced by atleast 5%, at least 10%, at least 15%, at least 20%, at least 25%, atleast 30%, at least 35%, at least 40%, at least 45%, at least 50%, ormore, as compared to what would be expected in the absence of themethod. An A1AR agonist or other agent that stimulates AP musclecontraction, such as a muscarinic receptor agonist, a nicotinic receptoragonist, and/or a cholinesterase inhibitor, can be present on the brushor comb used for the brushing or combing. In one embodiment, the A1ARagonist or other agent (e.g., a muscarinic receptor agonist, a nicotinicreceptor agonist, and/or a cholinesterase inhibitor) can be applied tothe brush or comb prior to brushing or combing, e.g., in the form of aliquid, gel, cream or spray. In one embodiment, the brush or comb candispense the A1AR agonist or other active agent.

Agents that promote the contraction of the AP muscle can optionally beadministered by iontophoresis, which uses an electric field to drive thepassage of ionic agents or drugs into the skin. As but one example,iontophoresis has been used to deliver agents such as phenylephrine tothe skin to stimulate AP muscle contraction (See, e.g. Siepmann et al.,Neurology April 25, 2012; 78(Meeting Abstracts 1): P05.197). Thus, inone embodiment, a brush or comb can incorporate an iontophoresis device,which can dispense the A1AR agonist or other agent and/or be used fortransdermal delivery of the agent(s). The iontophoresis device cancomprise one or more metal contacts. Optionally, the iontophoresisdevice can comprise one or more compartments for containing the A1ARagonist or other agent(s). For example, the iontophoresis device cancomprise one or more compartments for containing at least one of an A1ARagonist, a muscarinic receptor agonist, a nicotinic receptor agonist,and/or a cholinesterase inhibitor.

In another aspect, the condition in which at least one hair follicle isunder tension is a hair-related cosmetic procedure. Accordingly, thetechnology described herein relates to a method of reducing hairshedding during a hair-related cosmetic procedure. Examples ofhair-related cosmetic procedures include, but are not limited to,brushing, braiding, flat ironing, and combinations thereof.

In another aspect, the condition in which at least one hair follicle isunder tension is trichotillomania, a disorder characterized by thecompulsive urge to pull out one's hair. Accordingly, to the extent thatincreasing the force required to remove the hair can help counter hairloss due to this condition, the stimulation of AP muscle contraction asdescribed herein can provide a method to reduce the hair loss.

Electrical Stimulation

In another embodiment of the invention, the AP muscle can be contractedvia electrical stimulation to the scalp or dermis of the skull. Theelectrical stimulation can be controlled, e.g., by a unit contained in abrush or a comb, or, e.g., embedded in a hair extension. In someembodiments, the control unit can contain an accelerometer to detect theoptimal time to contract the AP muscles based on the posture of thesubject or the subject's hair. In some embodiments, a strain or otherforce gauge attached to a portion of a hair extension can test the forcepulling on the patient's hair. Then, the electrical stimulator couldvary the amount of current, voltage or other component of the electricalstimulation applied to vary the strength of smooth muscle contractionbased on the amount of force pulling on the hair at a certain time. Inother embodiments, the control unit can deliver a standard amount ofcurrent to the hair in order to reach the electrical threshold forcontraction of the AP muscle. This can advantageously minimize theamount of current being applied to the scalp overall and the amount ofelectricity. Accordingly, one advantage of utilizing electricalstimulation to contract the muscle, is that the strength of thecontraction can be varied accordingly.

Examples of applying electrical forces to contract the AP muscles aredescribed in, for example, US Patent Publication US20 13/0199348published on Aug. 8, 2013, titled Pilomotor Effect Stimulating Deviceand Method, which is incorporated by reference herein in its entirety.For example, in some embodiments, the voltage or amplitude of the signalapplied to the scalp can be in the range of 35 to 75 volts, 25 to 50volts, 10-30 volts or other suitable ranges to reach the threshold formuscle contraction. The current applied to a scalp by a device asdisclosed herein can, in some embodiments, preferably be in themicroamps to avoid electrocution of the user. A frequency of 10 KHz to15 KHz can be applied, or a lower or higher frequency. In someembodiments, the pulse length applied will be from 1 to 50 milliseconds,1 to 100 milliseconds, or other suitable lengths to contract the APmuscle or any other pilomotor effective amount of current. In someembodiments, a control unit will automatically pulse the electricalstimulation at random intervals that are enough to keep the AP musclerelatively contracted. In other embodiments, the pulses will be spacedout enough to allow the AP muscle to relax in between pulses.

The disclosure also concerns a device for hair augmentation andprevention of traction alopecia comprising: a hair augmentation device;and an electrical stimulation device connected to the hair augmentationdevice, the electrical stimulation device comprising: a battery; amemory; an electrical stimulation generator; a scalp probe in electricalcommunication with the electrical stimulation generator for applying anelectrical stimulus; and a controller in communication with the battery,memory, and electrical stimulation and memory wherein the controllercommands the electrical stimulus generator to output a pilomotoreffective amount of electrical stimulus. In certain embodiments, thepilomotor effective amount of electrical stimulus is between 10-100volts, or between 10-15 kHz. In some embodiments the pilomotor effectiveamount of electrical stimulus is applied for 1 to 100 milliseconds. Insome embodiments, the pilomotor effective amount of electrical stimulusis applied periodically with rest periods long enough to allow the APmuscle to relax between stimuli. In other embodiments, the pilomotoreffective amount of electrical stimulus is applied periodically withrest periods short enough to prevent the AP muscle from relaxing betweenstimuli. The hair augmentation device may be any product that whenapplied to the hair exelts a pulling force on the hair. For example, thehair augmentation device may be a hair extension, a weave, or abarrette.

In some embodiments, a probe or electrical prongs can be attached to ahair extension or other hair piece that would deliver the charge to thescalp. In some embodiments, the probe can be connected to a control unitwith an on switch, a processor, and memory with firmware or othersoftware instructions for delivering the desired pulses. Differentcontrol units can contain more advanced circuitry and algorithms forprocessing accelerometer or force data and varying the electricalstimulus accordingly. In some embodiments, the probe can be connected toany portion of a hair piece using any suitable apparatus and method.

Other Agents or Approaches to Contract the Smooth Muscle

Other agents or approaches can be used to contract the smooth muscle forthe prevention or treatment of alopecia, e.g., traction alopecia. Asnoted above, any agent or treatment that stimulates AP musclecontraction is of potential use in methods of treating, reducing orpreventing alopecia as described herein.

In one embodiment, the smooth muscle can be contracted by stimulating oractivating a cold receptor. A cold receptor can be stimulated, forexample, by activating the TRPM8 channel. Exemplary agents that canstimulate a cold receptor include, but are not limited to, menthol andicilin. Compositions and methods for stimulating a cold receptor aredisclosed, for example, in U.S. Pat. No. 4,034,109, the contents ofwhich are incorporated by reference in its entirety.

Where the AP muscle is served by or associated with both noradrenergicfibers and a cholinergic system, agents that stimulate release oftransmitters from these systems can be used to stimulate AP musclecontraction. Thus, not only alpha 1 adrenergic receptor agonists, butalso cholinergic receptor agonists, including, but not limited toacetylcholine and other neurotransmitters that stimulate smooth musclecontraction are contemplated for use in the methods and compositionsdescribed herein.

The arrector pili muscle is innervated by sympathetic adrenergic as wellas sympathetic cholinergic neurons. Primer on the Autonomic NervousSystem, third Edition, Edited by David Robertson, Italo Biaggioni, Page415. The adrenergic neurons release norepinephrine (NE), which binds toalpha-1 adrenergic receptors to induce piloerrection. The cholinergicneurons release acetylcholine (ACh), which binds primary to muscarinicacetylcholine receptors mAChRs (predominantly M₃ and possibly M₂, seeEglen R M et al., “Muscarinic acetylcholine receptor subtypes in smoothmuscle,” Trends Pharmacol Sci 1994 April; 15(4):114-9) to inducepiloerrection. Thus, the inventive method provides an alternativemechanism of action to that of the A1AR agonists in the treatment oftraction alopecia, and this alternative mechanism provides forincreasing the epilatory force required to pull hair or reducing hairshedding during cosmetic procedures that apply force on the hair root.

The alpha 1 adrenergic receptor is a G protein-coupled receptor.Agonists of other G protein-coupled receptors (e.g., alpha 2 adrenergicreceptor) can also be used to stimulate contraction of the smoothmuscle. Examples of alpha 2 adrenergic receptor agonists include, butare not limited to, 4-NEMD, 7-Me-marsanidine, agmatine, apraclonidine,brimonidine, clonidine, detomidine, dexmedetomidine, fadolmidine,guanabenz, guanfacine, lofexidine, marsanidine, medetomidine,methamphetamine, mivazerol, rilmenidine, romifidine, talipexole,tizanidine, tolonidine, xylazine, and xylometazoline. As noted above, tothe extent that it would be disadvantageous to administer these or otheragents systemically, they can be administered in a formulation thatpermits uptake by the AP muscle in the dermis but limits systemicuptake.

In one embodiment, halostachine (also known asN-methylphenylethanolamine) is contemplated for use as a therapeuticagent in the methods and compositions described herein to stimulatesmooth muscle contraction.

It should be noted that agonists described herein also encompass theirinorganic or organic salts. Representative salts include thehydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate,acetate, succinate, valerate, oleate, palmitate, stearate, laurate,benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate,and laurylsulphonate salts and the like.

It should be noted that combinations of the above methods and agents canbe used to promote the contraction of the smooth muscle.

Treatment of Acne

The compositions described herein can also be used for the treatment ofacne. It is known that contraction of the AP muscle plays a role in thesecretion of the sebum (see Mahfouz et al., J. Egypt wom. Dermatol. Soc.2005, 2, 25-29). The compositions can be applied in the form of lotion,cream, spray, or wipe. The compositions can be used in combination withbenzoyl peroxide or other topical medications for acne treatment.

Representative Methods

In an exemplary embodiment, a method for treatment or prevention oftraction alopecia can include applying a composition comprising apilomotor effective amount of a muscarinic receptor agonist, a nicotinicreceptor agonist, or a cholinesterase inhibitor topically to a portionof skin on the head that includes at least one hair follicle. In someembodiments, the at least one hair follicle is under tension. In someembodiments, the portion of skin is at risk for developing tractionalopecia. In some embodiments, the composition comprises a muscarinicacetylcholine receptor agonist. In some embodiments, the composition orthe method of treatment further comprises a second active agent orapplying a second active agent, such as without limitation an alpha 1adrenergic receptor agonist.

In another exemplary embodiment, a method of reducing hair sheddingduring brushing, combing or showering can include applying a compositioncomprising a pilomotor effective amount of a muscarinic receptoragonist, a nicotinic receptor agonist, and/or a cholinesterase inhibitortopically to a portion of skin on the head that includes at least onehair follicle. In some embodiments, the composition is applied to theskin prior to the brushing or combing. In some embodiments, the at leastone hair follicle is under tension. In some embodiments, the compositioncomprises a muscarinic acetylcholine receptor agonist. In someembodiments, the composition or method further comprises a second activeagent or administering a second active agent, such as without limitationan alpha 1 adrenergic receptor agonist.

In another exemplary embodiment, a method for increasing epilatory forceof the hair can include applying a composition comprising a pilomotoreffective amount of at least one of a muscarinic receptor agonist, anicotinic receptor agonist, and/or a cholinesterase inhibitor topicallyto a portion of skin on the head of a person that includes at least onehair follicle. In some embodiments, before, during or after thecomposition is applied, the person undergoes a cosmetic procedure to thehair selected from the group consisting of braiding, flat ironing,attaching a hair weave, attaching a hair extension, or tying the hairback in a ponytail. In some embodiments, the composition comprises anagonist of (1) a muscarinic M₂-type receptor, (2) a muscarinic M₃-typereceptor, (3) a N_(N)-type receptor, and/or (4) a N_(M)-type receptor,and/or comprises a cholinesterase inhibitor. In some embodiments, thecomposition comprises a muscarinic acetylcholine receptor agonist. Insome embodiments, the composition further comprises an alpha 1adrenergic receptor agonist. In some embodiments, the composition isapplied to the skin once daily. In some embodiments, the composition isapplied to the skin twice daily.

In another exemplary embodiment, method for prevention of tractionalopecia can include applying a composition comprising a pilomotereffective amount of at least one of a muscarinic receptor agonist, anicotinic receptor agonist, and/or a cholinesterase inhibitor to thescalp to an area with a group of follicles that will experience apulling force from a hair augmentation device. The method can furtherinclude attaching the hair augmentation device to the group offollicles.

The various methods and techniques described above provide a number ofways to carry out the invention. Of course, it is to be understood thatnot necessarily all objectives or advantages described can be achievedin accordance with any particular embodiment described herein. Thus, forexample, those skilled in the art will recognize that the methods can beperformed in a manner that achieves or optimizes one advantage or groupof advantages as taught herein without necessarily achieving otherobjectives or advantages as taught or suggested herein. A variety ofalternatives are mentioned herein. It is to be understood that someembodiments specifically include one, another, or several features,while others specifically exclude one, another, or several features,while still others mitigate a particular feature by inclusion of one,another, or several advantageous features.

Furthermore, the skilled artisan will recognize the applicability ofvarious features from different embodiments. Similarly, the variouselements, features and steps discussed above, as well as other knownequivalents for each such element, feature or step, can be employed invarious combinations by one of ordinary skill in this art to performmethods in accordance with the principles described herein. Among thevarious elements, features, and steps some will be specifically includedand others specifically excluded in diverse embodiments.

Although the application has been disclosed in the context of certainembodiments and examples, it will be understood by those skilled in theart that the embodiments of the application extend beyond thespecifically disclosed embodiments to other alternative embodimentsand/or uses and modifications and equivalents thereof.

The recitation of ranges of values herein is merely intended to serve asa shorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (for example, “such as”) provided withrespect to certain embodiments herein is intended merely to betterilluminate the application and does not pose a limitation on the scopeof the application otherwise claimed. No language in the specificationshould be construed as indicating any non-claimed element essential tothe practice of the application.

Certain embodiments of this application are described herein. Variationson those embodiments will become apparent to those of ordinary skill inthe art upon reading the foregoing description. It is contemplated thatskilled artisans can employ such variations as appropriate, and theapplication can be practiced otherwise than specifically describedherein. Accordingly, many embodiments of this application include allmodifications and equivalents of the subject matter recited in theclaims appended hereto as permitted by applicable law. Moreover, anycombination of the above-described elements in all possible variationsthereof is encompassed by the application unless otherwise indicatedherein or otherwise clearly contradicted by context.

All patents, patent applications, publications of patent applications,and other material, such as articles, books, specifications,publications, documents, things, and/or the like, referenced herein arehereby incorporated herein by this reference in their entirety for allpurposes, excepting any prosecution file history associated with same,any of same that is inconsistent with or in conflict with the presentdocument, or any of same that can have a limiting affect as to thebroadest scope of the claims now or later associated with the presentdocument. By way of example, should there be any inconsistency orconflict between the description, definition, and/or the use of a termassociated with any of the incorporated material and that associatedwith the present document, the description, definition, and/or the useof the term in the present document shall prevail.

EXAMPLES Example 1 Oxymetazoline HCl at 0.1%, 0.2%, 0.5% by Weight

A study was conducted to assess the dosage of topical oxymetazolinesolution required to elicit the pilomotor reflex of the hairarrector-pili muscle. Five subjects participated in the study. Threeformulations were used: Formula A: 0.1% topical oxymetazolinehydrochloride solution; Formula B: 0.2% topical oxymetazolinehydrochloride solution; Formula C: 0.5% topical oxymetazolinehydrochloride solution.

The study was conducted over 3 days. On day 1, subjects were instructedto apply Formula A to their arm. On day 2, subjects were instructed toapply Formula B to their arm. On day 3, subjects were instructed toapply Formula C to their arm. 0.1 mL of each formula was applied using ametered dosage dispenser to each arm. Table 1 summarizes the findingfrom this study.

TABLE 1 Oxymetazoline study Subject No. Formula A Formula B Formula C 1NR NR R 2 NR NR R 3 NR NR R 4 NR NR R 5 NR NR R R = Response, i.e. goosebumps; NR = No response

Table 1: Oxymetazoline Study

The 0.5% topical oxymetazoline solution (Formula C) elicited a clinicalresponse in all subjects while the 0.1% and 0.2% formulations (Formula Aand B) failed to elicit a response. With the 0.5% topical oxymetazolinesolution, response in the contraction of the arrector.pilomotor musclewas obtained approximately within 1 hour and lasted over 8 hours.

Due to the long acting effect of oxymetazoline it may be beneficial toapply once daily, every other day, or as needed prior to mechanicalprocedures that may exert epilatory forces on hair follicles.

Example 2 Phenylephrine HCl at 5.0%, 7.5%, 10% by Weight

A study was conducted to assess the dosage of topical phenylephrinesolution required to elicit the pilomotor reflex of the hairarrecto-pili muscle. Five subjects participated in the study. Threeformulations were used: Formula A: 5.0% topical phenylephrinehydrochloride solution; Formula B: 7.5% topical phenylephrinehydrochloride solution; Formula C: 10.0% topical phenylephrinehydrochloride solution.

The study was conducted over 3 days. On day 1, subjects were instructedto apply Formula A to their arm. On day 2, subjects were instructed toapply Formula B to their arm. On day 3, subjects were instructed toapply Formula C to their arm. 0.1 mL of each formula was applied using ametered dosage dispenser to each arm. Table 2 summarizes the findingfrom this study.

TABLE 2 Phenylephrine study - 1 Subject No. Formula A Formula B FormulaC 1 NR NR R 2 NR NR R 3 NR NR R 4 NR NR R 5 NR NR R R = Response, i.e.goose bumps; NR = No response

The 10.0% topical phenylephrine solution (Formula C) elicited a clinicalresponse in all subjects while the 5.0% and 7.5% formulations (Formula Aand B) failed to elicit a response. With the 10.0% topical phenylephrinesolution, response in the contraction of the arrector-pilomotor musclewas obtained approximately within 20-30 minutes and lasted over 3 hours.

Due to the shorter lasting acting effect of phenylephrine compared tooxymetazoline it may be beneficial to apply as needed prior tomechanical procedures that may exert epilatory forces on hair follicles.

Example 3 Phenylephrine HCl at 10% by Weight

In another study, 10.0% phenylephrine hydrochloride to assess the use oftopical phenylephrine hydrochloride solution as a novel drug forprevention/reduction of hair loss from mechanical pulling. Participantsincluded in the study were female subjects between ages of 18 and 60 whofrequently use traumatic hair care practices, such as tight braids, headscarves, ponytails, extensions, hair rollers, hair weaves and heatedstyling appliances such as blow dryers, flat irons, heat setters andcurling irons. Excluded subjects were those who experienced uncontrolledhypertension, those who were pregnant or breastfeeding, those who werediagnosed with pattern hair loss, or those who experienced other hairloss in conjunction with female pattern hair loss. Overall, fifteenfemale subjects, aged 24 to 40 years, participated in the study.

The study was conducted over 4 days. On day 1, subjects were instructedto wash their hair. On day 2, subjects were instructed to apply 1 mL ofplacebo solution containing vehicle and brush targeted area after 30minutes. Brushing was conducted to frontal hair with regular brush insize of 8×10 cm. On day 3, subjects were instructed again to wash theirhair. On day 4, subjects were instructed to apply 1 mL of 10%phenylephrine hydrochloride solution on targeted area and brush after 30minutes. FIGS. 2-5 summarize the finding from this study.

FIGS. 2 and 3 show that application of the 10% phenylephrinehydrochloride solution resulted in reduced hair shedding in 80% of thepatients, as compared to the placebo solution containing the vehicle,with the average reduction being approximately 42%. FIGS. 4 and 5 showthat the epliatory force threshold for plucking hair follicles followingtopical 10% phenylephrine hydrochloride application increased byapproximately 172%. Therefore, there is a significant reduction hairloss from mechanical pulling and increase in epilatory force aftertopical application of 10% phenylephrine hydrochloride. This novel studydemonstrates the utility of alpha-1-AR agonists in the treatment oftraction alopecia and excessive hair loss resulting from mechanicalcosmetic procedures.

Example 4 Synephrine HCI at 40%,50% by Weight

A study was conducted to assess the dosage of topical synephrinesolution required to elicit the pilomotor reflex of the hairarrecto-pili muscle. Five premenopausal subjects participated in thestudy. Two formulations were used: Formula A: 40% topical synephrinehydrochloride solution; Formula B: 50% topical synephrine hydrochloridesolution in both of which solutions the synephrine was present inapproximately a racemic mixture of (+/−) synephrine HCl.

The study was conducted over 2 days. On day 1, subjects were instructedto apply Formula A to their arm. On day 2, subjects were instructed toapply Formula B to their ann. 0.1 mL of each formula was applied using ametered dosage dispenser to each arm. Table 3 summarizes the findingfrom this study.

TABLE 3 Synephrine study Subject No. Formula A Formula B 1 NR R 2 NR R 3NR R 4 NR NR 5 NR R R = Response, i.e. goose bumps; NR = No response

The 50% topical synephrine hydrochloride solution (Formula B) elicited aclinical response in 4 out of 5 subjects while Formula A failed toelicit a response.

Example 5 Phenylephrine

Female subjects, ages 18-40, were recruited to study the effect oftopically applied phenylephrine, a selective α1-AR agonist, on epilationforce and hair shedding during cosmetic procedures. In the blindedstudy, 80% of subjects demonstrated reduced shedding on days usingphenylephrine compared to days using a placebo solution. The averagereduction in hair loss was approximately 42%. In addition, the forcethreshold required for epilation increased by approximately 172%following topical phenylephrine application. To our knowledge this isthe first study demonstrating the utility of α1-AR agonists in thetreatment of traction alopecia and hair shedding during cosmeticprocedures.

Methods:

Patients: Fifteen female subjects, ages 18-40, were included in thestudy. Subjects were recruited based on their frequent use of traumatichair care practices, such as, tight braids, head scarves, ponytails,extensions, hair rollers, hair weaves and heated styling appliances suchas blow dryers, flat irons, heat setters and curling irons. Subjectswith uncontrolled hypertension, that were pregnant or breastfeeding, hadbeen diagnosed with pattern hair loss or with other hair loss inconjunction with female pattern hair loss were excluded from the study.Prior to initiating the study, the efficacy of the 10% phenylephrinesolution was tested by applying a small aliquot (50 μL) of the solutionto the forearm of three subjects. Piloerection and blanching werevisible after 30 minutes; the effect lasted for approximately 2-3 hours.

Hair Shedding: To measure hair loss during cosmetic procedures, a 4-dayprotocol was designed. On the first day patients were instructed to washtheir hair and use styling products and procedures as they normallywould. On the second day, patients were instructed not to wash theirhair and to apply 0.5 mL of a placebo solution, containing a vehicleonly, on the frontal area of the scalp in an 8×10 cm² target area.Patients were instructed to wait 45 minutes, after which, they brushedtheir hair 20 times from the front of the scalp to the bottom of headusing a new brush. After the procedure, the brushes were sealed in aplastic bag. On day three, patients were instructed to wash their hairand use styling products and procedures as they normally would. On thefourth day, patients repeated the procedures of day two; only theyapplied 0.5 mL of a 10% phenylephrine solution to the target area. Aftereach clinical procedure, the investigator counted the hairs collected oneach brush. A new brush was used for each procedure.

Epilation Force:

To evaluate the effect of a topically applied α1-AR agonist on the forcerequired to pluck hairs from the scalp, a hand-held spring dynamometer,or “trichotillometer” was used (8). The trichotillometer records themaximum force threshold, in grams, required to pluck a single hair fromthe scalp; the performance and statistical variance of the instrumenthave been reported previously (8-10). Force measurements were performedusing the trichotillometer on 10 subjects. The frontal area of scalp wasdivided into two 8×10 cm2 areas. On the right side 0.5 mL of a placebovehicle was applied. On the left side, 0.5 mL a 10% phenylephrinesolution was applied. After 45 minutes, ten hairs were plucked from eachof the target areas with the trichotillometer.

Results:

After tabulating the data of 15 subjects studied in the hair sheddingexperiment (Table 4), we found a decrease in hair loss in 12 out of 15patients (80% ) in the target area following the application of 10%phenylephrine solution compared to hair loss in the targeted areafollowing the application of a placebo solution. Reduction in the hairloss varied from 9% to 100%, with an average reduction of 42%.

TABLE 4 Table 4. Number of hairs removed with brush after theapplication of 10% phenylephrine (10% PE) or placebo. Patient Number ofHairs Removed with Brush # Placebo 10% PE Reduction 1 35 16 54% 2 3 0100%  3 10 10  0% 4 14 8 43% 5 28 17 39% 6 31 11 65% 7 3 2 33% 8 12 650% 9 5 2 60% 10 35 32  9% 11 28 8 71% 12 2 2  0% 13 7 7  0% 14 8 2 75%15 7 5 29% AVERAGE 42%

Measurements of the epilation force threshold in 10 subjects showedsimilar improvements (Table 5). The epilation force threshold on scalphair follicles increased 172% on average (range: 5% to 462% ) followingthe application of a topical 10% phenylephrine solution.

TABLE 5 Table 5. Grams of force required for epilation after theapplication of 10% phenylephrine (10% PE) or placebo. Each data point isthe average of 10 plucked hairs [avg. (std.)]. Patient Epilation Force(grams) # Placebo 10% PE Reduction 1 2.6 (2.6) 13.0 (6.6) 400% 2 16.6(2.7) 24.8 (2.9)  49% 3 15.2 (2.4) 34.8 (2.9) 129% 4 6.8 (6.4) 26.0(7.9) 282% 5 2.6 (1.5) 14.6 (4.8) 462% 6 18.0 (3.2)  23.6 (11.1)  31% 717.6 (4.4) 18.4 (2.3)  5% 8 14.6 (4.2) 20.4 (4.6)  40% 9 11.2 (5.9) 22.0(5.5)  96% 10 9.4 (4.8) 30.2 (8.3) 221% AVERAGE 172%

Discussion:

At present, many people use various mechanical hair procedures, whichresult in increased traumatic force on hair follicles and result intraction alopecia. Each hair follicle in the human skin contains anarrector pili muscle, which expresses al adrenergic receptors (α1-AR).Stimulation of the arrector pili muscle with α1-AR agonist causescontraction of the muscle, which can provide a counterforce to resistepilation of hair follicles. In this experiment, we demonstrated that a10% solution of phenylephrine, a selective al agonist, could inducepiloerection on the scalp that reduced hair shedding and increased thethreshold force for epilation. To our knowledge this is the first studyelucidating the novel mechanism of α1-AR agonist induced piloerectionfor the treatment of traction alopecia and excessive hair sheddingresulting from cosmetic procedures.

Example 6 Bitter Orange Extract

Highly purified (greater than 90% ) natural bitter orange extract fromCitrus aurantium was tested at 25% and 12.5% in a buffer solution atpH5.2 on the arms of four subjects to determine piloerection response.The 12.5% dosage failed to elicit a response. The 25% solution eliciteda response. The response appeared after about 15-30 minutes. Thepiloerection lasted 3-4 hours.

REFERENCES

1. Ozyelik D. Extensive traction alopecia attributable to ponytailhairstyle and its treatment with hair transplantation. Aesthetic PlastSurg 2005: 29(4): 325-327.2. Hjorth N. Traumatic marginal alopecia; a special type: alopeciagroenlandica. Br J Dermatol 1957: 69(9): 319-322.3. Khumalo N P, Jessop S, Gumedze F, Ehrlich R. Determinants of marginaltraction alopecia in African girls and women. JAm Acad Dermato12008:59(3): 432-438.4. Hellmann K. The isolated pilomotor muscles as an in vitropreparation. J Physiol 1963: 169: 603-620.5. Siepmann T, Gibbons C H, Illigens B M, Lafo J A, Brown C M, FreemanR. Quantitative pilomotor axon reflex test: a novel test of pilomotorfunction. Arch Neurol2012: 69(11): 1488-1492.6. Lewis T, Marvin H M. Observations upon a pilomotor reaction inresponse to faradism. J Physiol1927: 64(1): 87-106.7. Piascik M T, Perez D M. Alphal-adrenergic receptors: new insights anddirections. J Pharmacal Exp Ther 2001: 298(2): 403-410.8. Wyness L A, McNeill G, Prescott G L. Trichotillometry: thereliability and practicality of hair pluckability as a method ofnutritional assessment. Nutr J 2007:6:9.9. Chase E S, Weinsier R L, Laven G T, Krumdieck C L. Trichotillometry:the quantitation of hair pluckability as a method of nutritionalassessment. Am J Clin Nutr 1981: 34(10): 2280-2286.10. Smelser D N, Smelser N B, Kmmdieck C L, Schreeder M T, Laven G T.Field use of hair epilation force in nutrition status assessment. Am JClin Nutr 1982: 35: 342-346.

1. A method for treatment or prevention of traction alopecia comprisingapplying a pilomotor effective amount of an active agent selected fromthe group consisting of muscarinic receptor agonists, nicotinic receptoragonists, and cholinesterase inhibitors topically to a portion of skinon the head that includes at least one hair follicle.
 2. The method ofclaim 1, wherein the at least one hair follicle is under tension.
 3. Themethod of claim 1, wherein the portion of skin is at risk for developingtraction alopecia.
 4. The method of claim 1, wherein the active agent isselected from the group consisting of agonists of muscarinic M₂-typereceptors, agonists of muscarinic M₃-type receptors, agonists of aN_(N)-type receptor, agonists of a N_(M)-type receptor, andcholinesterase inhibitors.
 5. The method of claim 1, wherein the activeagent is a muscarinic receptor agonist.
 6. The method of claim 1,further comprising administering a therapeutically effective amount ofan agonist of an alpha 1 adrenergic receptor topically to the portion ofskin on the head.
 7. A method of reducing hair shedding during brushing,combing or showering, the method comprising applying a pilomotoreffective amount of an active agent selected from the group consistingof muscarinic receptor agonists, nicotinic receptor agonists, andcholinesterase inhibitors topically to a portion of skin on the headthat includes at least one hair follicle.
 8. The method of claim 7,wherein the composition is applied to the skin prior to the brushing orcombing.
 9. The method of claim 7, wherein the at least one hairfollicle is under tension.
 10. The method of claim 7, wherein the activeagent is selected from the group consisting of agonists of muscarinicM₂-type receptors, agonists of muscarinic M₃-type receptors, agonists ofa N_(N)-type receptor, agonists of a N_(M)-type receptor, andcholinesterase inhibitors.
 11. The method of claim 7, wherein thecomposition comprises a muscarinic acetylcholine receptor agonist. 12.The method of claim 7, further comprising administering atherapeutically effective amount of an agonist of an alpha 1 adrenergicreceptor topically to the portion of skin on the head.
 13. A method forincreasing epilatory force of the hair, the method comprising applying apilomotor effective amount of an active agent selected from the groupconsisting of muscarinic receptor agonists, nicotinic receptor agonists,and cholinesterase inhibitors topically to a portion of skin on the headof a person that includes at least one hair follicle.
 14. The method ofclaim 13, wherein before, during or after the active agent is applied,the person undergoes a cosmetic procedure to the hair selected from thegroup consisting of braiding, flat ironing, attaching a hair weave,attaching a hair extension, or tying the hair back in a ponytail. 15.The method of claim 13, wherein the active agent is selected from thegroup consisting of agonists of muscarinic M_(2-type) receptors,agonists of muscarinic M₃-type receptors, agonists of a N_(N)-typereceptor, agonists of a N_(M)-type receptor, and cholinesteraseinhibitors.
 16. The method of claim 13, wherein the active agent is amuscarinic receptor agonist.
 17. The method of claim 13, furthercomprising administering a therapeutically effective amount of anagonist of an alpha 1 adrenergic receptor topically to the portion ofskin on the head.
 18. The method of claim 13, wherein the active agentis applied to the portion of the skin once daily.
 19. The method ofclaim 13, wherein the composition is applied to the portion of the skintwice daily.
 20. A method for prevention of traction alopeciacomprising: applying a composition comprising a pilomoter effectiveamount of an active agent selected from the group consisting ofmuscarinic receptor agonists, nicotinic receptor agonists, andcholinesterase inhibitors to the scalp to an area with a group offollicles that will experience a pulling force from a hair augmentationdevice; and attaching the hair augmentation device to the group offollicles.